Conn Syndrome Workup

Routine laboratory studies can show hypernatremia, hypokalemia, and metabolic alkalosis resulting from the action of aldosterone on the distal tubule of the kidney (ie, enhancing sodium reabsorption and potassium and hydrogen ion excretion).

Almost 20% of patients have impaired glucose tolerance resulting from the inhibitory effect of hypokalemia on insulin action and secretion; however, diabetes mellitus is rare.

Normokalemia does not exclude primary hyperaldosteronism. Several studies have shown that 7-38% of patients with primary hyperaldosteronism have baseline serum levels of potassium that are in the reference range. The hypokalemia becomes evident with liberalization of dietary sodium intake.

Postural studies

Postural studies are cumbersome to perform in most office settings and have proven less useful since the recognition of a renin-responsive subtype of adrenal adenoma. They are rarely used in current practice.

Typically, renin levels are suppressed to less than 1 ng/mL/h in patients with primary hyperaldosteronism, and levels do not stimulate above 2 ng/mL/h with diuretics and upright posture. Because of this finding, some experts suggest that suppressed renin levels should be used as a screen for detecting primary hyperaldosteronism. However, in a 1993 series by Bravo, 30% of patients had renin levels that rose to greater than 2 ng/mL/h when appropriately stimulated by sodium deprivation.^[3]

Thus, a nonsuppressed renin level in the setting of diuretic administration does not exclude a diagnosis of primary aldosteronism. Furthermore, a subnormal renin level (< 2 ng/mL/h) can be found in 30% of patients with essential hypertension; thus, a low renin level is not specific for primary aldosteronism.

In order to improve the sensitivity of a screening test for primary hyperaldosteronism, a ratio of plasma aldosterone (PA) activity to plasma renin activity (PRA) can be calculated. A PA/PRA ratio (obtained in the morning) of 20 or greater (with a PA ≥15 ng/dL) provides a sensitivity of 100% and a specificity of 80%, indicating the need for further study. Others use a ratio of greater than 30 and a PA level of greater than 20 ng/dL, with a sensitivity of 90% and a specificity of 91%.^{[4, 5]}

Medication interference

Note, however, that this ratio should be calculated when the patient is not taking interfering medications. Spironolactone should be stopped for 6 weeks prior to testing. Eplerenone, another aldosterone receptor antagonist, can also interfere with testing and should be stopped for at least 2 weeks before testing.

Alpha blockers, such as doxazosin, do not interfere with the PA/PRA ratio. Beta blockers and calcium channel blockers do not affect the diagnostic accuracy of the ratio in most cases.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) can falsely elevate PRA, leading to a lower PA/PRA ratio; therefore, the presence of suppressed PRA in a patient treated with a diuretic or, especially, an ACE inhibitor or ARB, is a strong predictor for primary hyperaldosteronism.

Because of limited specificity, a positive screening test result should be followed by a confirmatory test.

When the PA/PRA ratio is 20 or greater, with a PA of 15 ng/dL or greater, confirmatory tests need to be performed. The most commonly used confirmatory test is a 24-hour urine aldosterone level obtained after 3 days of salt loading. The patient can be instructed to maintain a sodium intake of at least 200 mEq/day (1 teaspoon of salt 3 times daily) for 3 days.

Care must be taken to ensure that potassium stores are replete and that the patient is normokalemic at the time of testing, because hypokalemia can inhibit aldosterone release and salt loading can exacerbate hypokalemia.

A 24-hour aldosterone excretion rate of greater than 14 mcg (with a concomitant 24 h urine sodium >200mEq) is diagnostic of primary hyperaldosteronism.

Once the diagnosis of primary hyperaldosteronism has been confirmed, the next step is to determine the subtype and to identify surgically curable disease. For practical purposes, this means distinguishing between an adrenal adenoma and bilateral hyperplasia.^[6]

In general, patients with adenomas are younger than patients with hyperplasia and have more severe hypertension and hypokalemia, as well as higher urinary aldosterone levels, than do patients with hyperplasia. However, these clinical parameters are not reliable enough to accurately distinguish unilateral disease from bilateral disease.

Abdominal computed tomography (CT) scanning is considered the procedure of choice. Overall, CT scanning has a sensitivity of 67-85% in patients with primary hyperaldosteronism. (Magnetic resonance imaging [MRI] is not more sensitive than CT scanning.)

Some investigators suggest that when a solitary, unilateral macroadenoma (>1 cm) is detected in the setting of unequivocal hyperaldosteronism in a young patient, unilateral adrenalectomy is indicated.

Because of the age-dependent risk that a solitary unilateral adrenal macroadenoma may be a nonfunctioning adenoma, some experts believe that adrenal vein sampling^[6] should be performed in patients older than 40 years.

The problem arises with lesions that are smaller than 1cm, which may be missed by CT scanning. Furthermore, bilateral lesions are not always diagnostic of adrenal hyperplasia, because of the high incidence of adrenal incidentaloma. In these cases, adrenal vein sampling is the only way to make a firm diagnosis.

Scanning with iodine-131 (¹³¹ I) iodocholesterol (NP-59, a precursor of aldosterone) has also been used to detect unilateral, functional adrenal lesions. In experienced hands, NP-59 scanning has a sensitivity of 88%. However, this procedure is not widely available, requires careful patient preparation, is very expensive, and rarely detects lesions larger than 1.5 cm. (See the image below.)

Because of the difficulties in distinguishing hyperplastic lesions from adenomatous lesions, adrenal venous sampling^[6] has become the preferred diagnostic approach in patients with equivocal findings after CT scanning.^[7]

The adrenal veins are catheterized via a percutaneous femoral venous approach. Right and left venous catheters should be placed in the ipsilateral adrenal veins to prevent errors in handling the samples.

Blood is obtained from both adrenal veins and the inferior vena cava and is then assayed for aldosterone and cortisol. Cannulation of the right adrenal vein is technically difficult because of the short length of this vessel. The left adrenal vein is longer, allowing for more stable catheter placement.

In order to document the placement of the catheters within the adrenal veins, an adrenal-to–vena cava cortisol ratio (postcorticotropin) is obtained and should be greater than 5-10. Because the secretion of aldosterone from either an adenoma or hyperplasia may be pulsatile, samples are obtained under maximum stimulation following cosyntropin (corticotropin) infusion. Several different protocols have been used.

In a 1996 article, Doppman and Gill recommended a 250mcg bolus of corticotropin (Cortrosyn), followed by a corticotropin infusion, with samples collected at baseline and 15 minutes following the infusion.^[8] An aldosterone-to-cortisol ratio, postcorticotropin, can then be calculated for each sampling site. Most patients with a unilateral source of aldosterone have adrenal-to-adrenal aldosterone-to-cortisol ratios greater than 4. Ratios of less than 3 suggest hyperplasia, and values of 3-4 are considered to be indeterminate results.